Septic shock continues to be a worldwide public health problem in both adults and children. Septic shock is a heterogeneous syndrome, not a discrete disease entity. Baseline mortality risk is widely variable, making it a major confounder for the conduct of interventional clinical trials. Current trial designs include patients with low baseline mortality risk who are unlikely to benefit from novel interventions beyond standard care, as well as patients having an extremely high baseline mortality risk who may be beyond salvage even with novel interventions. This can dilute the effect size for an experimental intervention that has benefit for patients between these extremes who have a significant, but modifiable mortality risk. Thus, an important and unmet clinical gap in the field is the lack of a robust stratification tool specific for septic shock. This proposal seeks to directly address this gap. We have derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE). The biomarkers included in PERSEVERE were selected objectively based on extensive, discovery-oriented transcriptomic studies. Of note, the biomarkers are proteins measured in the blood compartment and are measured at the time of meeting clinical criteria for septic shock. We recently derived and validated the risk stratification model for adults using the same approach in 881 subjects from three different countries. The Adult Septic Shock Information and Stratification Technology (ASSIST) outperform both APACHE II and III. Consistent with our preliminary data, we propose that one application of ASSIST is to better inform the selection of patients for interventional clinical trials. In this competitive revision, we will test this concep by conducting a post hoc, risk-stratified analysis of the Protocolized Care for Early Septic Shock (ProCESS) Trial. The ProCESS Trial randomly allocated 1,341 adults with septic shock into one of three early resuscitation strategies: protocol-based early goal-directed therapy (EGDT); protocol-based standard therapy that did not require placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. An important component of the ProCESS trial was the banking of biological samples at multiple time points, coupled with extensive clinical annotations. Accordingly, the ProCESS trial has generated one the most extensive, contemporary clinical and biological repositories of adult septic shock available. In collaboration with the ProCESS Investigators, we will test the hypothesis that the potential benefits of protocolized care in patients with septic shock, relative to usual care, are dependent on baseline mortality risk as estimated by ASSIST. This focused, competitive revision represents a first step toward bridging two innovative, NIH-funded, sepsis research programs to address major gaps in the field. This highly focused effort will provide the foundation for more extensive collaborations in the near future. The major deliverable of this Aim is a direct test of the concept that baseline mortality risk-based selection is an effective means of conducting interventional clinical trials for septic shock.